Sensorineural hearing loss and vestibular disorders result primarily from the loss of sensory hair cells. The broad long-term goal of the proposed research is to develop methods for the treatment of sensorineural hearing loss and vestibular disorders based on understanding the molecular signals regulating hair-cell regeneration in avian and rodent models. Virtually nothing is known regarding the factors involved in the initiation and regulation of hair-cell genesis and differentiation in either the mature or developing inner ear. The experiments outlined in this proposal will test two specific hypotheses: (1) that growth factors are important in regulating the proliferation of hair-cell progenitors, and (2) that macrophages are important in initiating and regulating hair-cell regeneration, perhaps through their release of growth factors, cytokines, or proteases. The first hypothesis will be tested by (1) adding known growth factors to mature, cultured inner-ear epithelium and assessing the effects on cellular proliferation; (2) localizing growth factors and growth-factor receptors and their mRNA in normal and regenerating inner- ear epithelium; and (3) infusing growth factors into the in situ inner ear, and examining the effects on cellular proliferation. The hypothesis that macrophages are important in initiating and regulating the hair-cell regeneration response will be tested by determining whether media conditioned by activated monocytes can stimulate proliferation in cultured inner-ear sensory epithelia.